Functionalized non-phenolic amino acids and absorbable polymers therefrom

ABSTRACT

The present invention relates to compound of formula I, which are functionalized, non-phenolic amino acids, and polymers formed from the same. 
     
       
         
         
             
             
         
       
     
     Polymers formed from the functionalized amino acids are expected to have controllable degradation profiles, enabling them to release an active component over a desired time range. The polymers are also expected to be useful in a variety of medical applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority benefit under 35 U.S.C. §119(e)of U.S. Provisional Patent Application Ser. No. 60/824,293 filed Sep. 1,2006. The disclosure this application is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to functionalized non-phenolic amino acidsand absorbable polymers derived there from, which can be useful for avariety of medical purposes, including drug delivery, tissueengineering, stent coatings, stents, and implantable medical devices.

BACKGROUND OF THE INVENTION

Amino acids are the “building blocks” of the body. Besides buildingcells and repairing tissue, they form antibodies to combat invadingbacteria & viruses; they are part of the enzyme & hormonal system; theybuild nucleoproteins (RNA & DNA); they carry oxygen throughout the bodyand participate in muscle activity. When a protein is broken down bydigestion the result is 22 known amino acids. Eight are essential(cannot be manufactured by the body) the rest are non-essential (can bemanufactured by the body with proper nutrition).

U.S. Pat. No. 5,099,060 describes diphenolic monomers based on3-(4-hydroxyphenyl) propionic acid and L-tyrosine alkyl esters(desaminotyrosyl-tyrosine alkyl esters). Subsequent related patentsinvolve variations of this basic monomer structure. These monomers,although useful in many applications, have several limitations. Themonomers are insoluble in water, and therefore the polymers made fromthem are not readily resorbable. In other words, the previouslydescribed polymers prepared from the previously describedwater-insoluble monomers will not have any weight loss while thedegradation of the polymer backbone results in the loss of mechanicalstrength and reduction in the polymer molecular weight. The monomersalso provide two phenolic hydroxyl groups, limiting the resultingpolymers to be fully aromatic backbone structures, which may lead togood mechanical strength but slow degradation rate.

Poly(hydroxy acids), such as poly(glycolic acid) (PGA), poly(lacticacid) (PLA) and their copolymers are certainly the most widelyinvestigated synthetic, degradable polymers due to their establishedrecord of safety and FDA approval. Poly(amino acids) derived fromnaturally occurring .alpha.-L-amino acids form another major group ofdegradable polymers. Despite their apparent potential as biomaterials,poly(amino acids) have actually found few practical applications. Amajor problem is that most of the poly(amino acids) are highlyintractable (e.g., non-processible), which limits their utility.

Although several copolymers of hydroxy acids and amino acids have beenprepared and evaluated from a biological perspective, theirinvestigation as biomaterials has been rather limited. Helder et al., J.Biomed. Mater. Res., (24), 1005-1020 (1990) discloses the synthesis ofglycine and DL-lactic acid copolymers and the resulting in vitro and invivo degradation. The elegant synthesis of a copolymer derived fromlactic acid and lysine was reported by Barrera et al., Macromolecules,(28), 425-432 (1995). The lysine residue was utilized to chemicallyattach a cell-adhesion promoting peptide to the copolymer. Otherpolymers of amino acids and hydroxy acids are disclosed by U.S. Pat. No.3,773,737.

The three types of copolymers mentioned above are random copolymersprepared from cyclic monomers by ring-opening polymerization. Thecomposition of the copolymers is highly dependent on the relativereactivity of the two types of cyclic monomers and on the exactpolymerization conditions used. It is hard to control the compositionand hard to predict the polymer properties. Also, there may be largebatch-to-batch variations in the polymer microstructure and sequence.Furthermore, most previous reports described polymers of low molecularweight (M_(w)<10,000).

There are only a few degradable polymers for medical uses that have beensuccessfully commercialized. Poly(glycolic acid) (PGA), poly(lacticacid) (PLA), and their copolymers are representative examples. In viewof the limitations of these polymers, there still remains a need forbiodegradable, especially bioresorbable, polymers suitable for use astissue-compatible materials. For example, many investigators in theemerging field of tissue engineering have proposed to engineer newtissues by transplanting isolated cell populations on biomaterialscaffolds to create functional new tissues in vivo. Bioresorbablematerials, whose degradation and resorption rates can be tailored tocorrespond to the rate of tissue growth, are needed.

SUMMARY OF THE INVENTION

The present invention provides novel functionalized amino acids, whichare hydrolysable and can be useful for medical applications (e.g., drugdelivery and solvent for dissolving drugs).

The present invention also provides novel, absorbable polymers andco-polymers (e.g., polyesters, polyamides, polyester amides,polyurethanes, and polyanhydrides) derived from functionalized aminoacids. These polymers are expected to have controllable degradationprofiles.

The present invention also provides novel medical devices comprisingfunctionalized amino acids or polymers derived from functionalized aminoacids.

Other features of the present invention will be pointed out in thefollowing description and claims.

DETAILED DESCRIPTION OF THE INVENTION

Poly(hydroxy acids), such as PGA and PLA, are the most successfulsynthetic biomaterials. However, there are concerns about the acidity oftheir degradation products, their limited range of physicomechanicalproperties, and their simple chemical structure that does not providechemical attachment points for biological ligands, drugs, orcrosslinkers.

The present invention introduces novel functionalized amino acids andabsorbable polymers derived from them. The amino acids arefunctionalized with safe and biocompatible molecules (e.g., glycolicacid, lactic acid, caprolactone, and dioxanone). The novelfunctionalized amino acids of the present invention are expected to havecontrollable hydrolysis profiles, improved bioavailability, improvedefficacy, and enhanced functionality. Some of the functionalized aminoacids can be monomers from which polymers can be made that are usefulfor medical applications. For example, non-phenol containing amino acids(e.g., L-lysine) can be functionalized to form functionalized monomersthat can then be polymerized to form absorbable polymers (e.g.,polyesters, polyamides, polyester amides, polyurethanes, andpolyanhydrides). It can be advantageous for the monomers that are to bepolymerized to have at least two active sites (e.g., 2 or 3) forpolymerization. These active sites include hydroxyl, amino, andcarboxylic acid groups (e.g., two hydroxyl groups, a hydroxyl group anda carboxylic acid, a hydroxyl group and an amine group, a carboxylicacid group and an amino group, and two carboxylic acid groups). Thefunctionalized amino acids with at least two active sites can also becopolymerized with selected difunctional molecules (e.g., dicarboxylicacids, dialcohols, diisocyanates, amino-alcohols, hydroxy-carboxylicacids, and diamines) based on the starting functionalized amino acid toform absorbable polymers. The polymers (and copolymers) of the presentinvention can also be further reacted/polymerized to form additionaluseful polymers of the present invention.

The definitions and examples provided in this application are notintended to be limiting, unless specifically stated.

As described herein, the functionalized amino acids and polymers of thepresent invention are useful in medical applications/medical devices.Medical application/medical devices, as used herein, encompass medicaland biomedical applications and include all types of applicationsinvolved in the practice of medicine that would benefit from a materialthat decomposes harmlessly within a known period of time. Examplesinclude medical and surgical devices, which include drug deliverysystems (e.g., a site-specific or systemic drug delivery systems ormatrices), tissue engineering (e.g., tissue scaffold), stent coatings,stents, porous devices, implantable medical devices, molded articles(e.g., vascular grafts, stents, bone plates, sutures, implantablesensors, and barriers for surgical adhesion prevention), wound closuredevices (e.g., surgical clips, staples, and sutures), coatings (e.g.,for endoscopic instruments, sutures, stents, and needles), fibers orfilaments (which may be attached to surgical needles or fabricated intomaterials including sutures or ligatures, multifilament yarn, sponges,gauze, tubes, and sheets for typing up and supporting damaged surfaceabrasions), rods, films (e.g., adhesion prevention barriers), knittedproducts, foodstuffs, nutritional supplements, nutriceuticals,cosmetics, pharmaceuticals, biodegradable chewing gums, flavors,enhanced drugs, drug intermediates, cancer preventing agents,antioxidants, controlled release preparations, and solvents for drugs.Examples of knitted products, woven or non-woven, and molded productsinclude: burn dressings; hernia patches; medicated dressings; fascialsubstitutes; gauze, fabric, sheet, felt, or sponge for liver hemostasis;gauze bandages; arterial graft or substitutes; bandages for skinsurfaces; suture knot clip; orthopedic pins, clamps, screws, and plates;clips (e.g., for vena cava); staples; hooks, buttons, and snaps; bonesubstitutes (e.g., mandible prosthesis); intrauterine devices (e.g.,spermicidal devices); draining or testing tubes or capillaries; surgicalinstruments; vascular implants or supports; vertebral discs;extracorporeal tubing for kidney and heart-lung machines; and,artificial skin.

As used herein, “polymer” includes both polymers and copolymersdepending on the number of different monomers used.

The present invention provides novel functionalized amino acids offormula I or stereoisomers or pharmaceutically acceptable salts thereof:

wherein:

X is selected from:

—CH₂COO— (glycolic acid moiety);

—CH(CH₃)COO— (lactic acid moiety);

—CH₂CH₂OCH₂COO— (dioxanone moiety);

—CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety);

—(CH₂)_(y)COO— where y is selected from 2, 3, 4, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24; and,

—(CH₂CH₂O)_(z)CH₂COO— where z is selected from 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24;

Y represents a member selected from the group consisting of:

—COCH₂O— (glycolic ester moiety);

—COCH(CH₃)O— (lactic ester moiety);

—COCH₂OCH₂CH₂O— (dioxanone ester moiety);

—COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety);

—CO(CH₂)_(m)O— where m is selected from 2, 3, 4, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24; and,

—COCH₂O (CH₂CH₂O)_(n) — where n is selected from 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24;

R′ is hydrogen, benzyl, or a straight-chained or branched C₁₋₆ alkyl;

a and b are independently selected from 1, 2, 3, 4, provided that a+btotal from 2, 3, 4, 5, to 6;

Amino Acid is the remaining portion of an amino acid and has other thana hydroxy-phenyl substituent, wherein when the Amino Acid is ahydroxy-substituted amino acid, the hydroxyl moiety is represented by—O—(X)_(c)—R′ or —O—(Y)_(c)—R′, wherein c is selected from 0-4;

provided that:

-   -   a. when the remaining portion of the amino acid is CH₂ and        (X)_(a)—R′ is CH₂CO₂H, then (Y)_(b)—R′ is other than C(O)CH₂OH;        or,    -   b. when the remaining portion of the amino acid is CH₂ and        (Y)_(b)—R′ is    -   C(O)CH₂OH, then (X)_(a)—R′ is other than CH₂CO₂H.

The group represented by X is attached via its carbon terminus to theoxygen group of the amino acid. The group represented by Y is attachedvia its carbonyl terminus to the nitrogen group of the amino acid.

Amino Acid refers to the portion of an amino acid not shown in the givenformula. For example, in formula I, Amino Acid refers to the portion ofan amino acid excluding the shown amino and acid portions. The term“amino acid” will typically refer to an entire amino acid (e.g.,glycine) as opposed to the non-amino, non-acid portion of an amino acid.“Amino Acid” and “amino acid” in some instances may be usedinterchangeably. It will be clear in the context of the presentapplication whether the reference is to a portion of or an entire aminoacid.

The rate of hydrolysis of the functionalized amino acids will dependupon a number of factors, including the functionalization species usedand the number of functionalization species present on thefunctionalized amino acid (e.g., 2-6). Glycolic acid modified aminoacids should hydrolyze faster than dioxanone modifies ones, where aslactic acid and caprolactone modified amino acids should take muchlonger to hydrolyze than glycolic acid and dioxanone modified aminoacids. Furthermore, it is expected that the rate of hydrolysis willincrease with the increase in the value of a+b. Thus, the desired timerange may be obtained by altering the number and type offunctionalization species used to functionalize the amino acid.

The present invention provides novel functionalized amino acids offormula I, wherein the amino acid is selected from β-Alanine, Alanine,2-Aminobutyric Acid, 4-Aminobutyric Acid, 6-Aminobutyric Acidα-Aminobutyric Acid, α-Aminosuberic Acid, Arginine, Asparagine, Asparticacid, 4-Chlorophenylalanine, Citrulline, β-Cyclohexylalanine, Cystein,Cystine, 3,4-Dehydroproline, 2-Fluorophenylalanine,3-Fluorophenylalanine, 4-Fluorophenylalanine, Glutamic Acid, Glutamine,Glycine, Histidine, Homocitrulline, Homoserine, Hydroxyproline,β-Hydroxyvaline, Isoleucine, Leucine, Lysine, Methionine,4-Nitrophenylalanine, Norleucine, Norvaline, Ornithine, Penicillamine,Phenylalanine, Phenylglycine, Proline, Sarcosine, Serine,β-(2-Thienyl)alanine, Threonine, Tryptophan, and Valine.

The amino acids used in the present invention include all of thepossible stereoisomers (e.g., D, L, D/L), unless a specific isomer isidentified.

The present invention also provides novel functionalized amino acids offormula I wherein y is selected from 2, 3, and 4; z is selected from 2,3, and 4; m is selected from 2, 3, and 4; and n is selected from 2, 3,and 4.

The present invention also provides novel functionalized amino acids offormula I, wherein:

X is selected from:

—CH₂COO—;

—CH(CH₃)COO—;

—CH₂CH₂OCH₂COO—; and, —CH₂CH₂CH₂CH₂CH₂COO—;

Y is selected from:

—COCH₂O—;

—COCH(CH₃)O—;

—COCH₂OCH₂ CH₂O—;

—COCH₂CH₂CH₂CH₂CH₂O—; and,

a and b are independently selected from 1-2, provided that a+b totalfrom 2-4.

The present invention also provides novel functionalized amino acids offormula I, wherein:

R′ is selected from hydrogen, benzyl, and a straight-chained or branchedC₁₋₄ alkyl; and,

a and b are independently selected from 1-2, provided that a+b totalfrom 2-3.

The present invention also provides novel functionalized amino acids offormula I, wherein:

R′ is selected from hydrogen, benzyl, and CH₃; and,

a and b are 1.

The present invention also provides novel functionalized amino acids offormula I, wherein:

X is —CH₂COO—;

Y is —COCH₂O—;

R′ is selected from hydrogen, benzyl, and a straight-chained or branchedC₁₋₄ alkyl; and,

a and b are independently selected from 1-2, provided that a+b totalfrom 2-4.

The present invention also provides novel functionalized amino acids offormula I, wherein:

R′ is selected from hydrogen, benzyl, and CH₃; and,

a and b are 1.

The present invention also provides novel functionalized amino acids offormulas Ia and IIa, wherein:

wherein:

a, b, and c are independently selected from 1-4, provided that a+b+ctotal from 1-6;

Amino Acid is the remaining portion of a hydroxyl-substituted aminoacid, which has other than a hydroxy-phenyl substituent.

The present invention also provides novel functionalized amino acids offormulas Ia and IIa, wherein: the Amino Acid, including the shown aminoand acid groups, is selected from: Homoserine, Hydroxyproline,β-Hydroxyvaline, Serine, and Threonine.

The present invention also provides novel functionalized amino acids offormulas Ia and IIa, wherein:

X is selected from:

—CH₂COO—;

—CH(CH₃)COO—;

—CH₂CH₂OCH₂COO—; and,

—CH₂CH₂CH₂CH₂CH₂COO—;

Y is selected from:

—COCH₂O—;

—COCH(CH₃)O—;

—COCH₂OCH₂CH₂O—;

—COCH₂CH₂CH₂CH₂CH₂O—; and,

a, b, and c are independently selected from 1-2, provided that a+b+ctotal from 3-4.

The present invention also provides novel functionalized amino acids offormulas Ia and IIa, wherein:

R′ is selected from hydrogen, benzyl, and CH₃; and,

a, b, and c are 1.

The present invention also provides novel functionalized amino acids offormulas Ia and IIa, wherein:

X is —CH₂COO—;

Y is —COCH₂O—;

R′ is selected from hydrogen, benzyl, and a straight-chained or branchedC₁₋₄ alkyl; and,

a, b, and c are independently selected from 1-2, provided that a+b+ctotal from 3-4.

The present invention also provides novel functionalized amino acids offormulas Ia and IIa, wherein:

the compound is of formula Ia;

R′ is selected from hydrogen, benzyl, and CH₃; and,

a, b, and c are 1.

The functionalized amino acids of the present invention can bepolymerized via conventional polymerization process using diol, triols,dicarboxylic acids, tricarboxylic acids, diamines, or triamines based onthe starting difunctionalized or trifunctionalized amino acids,including those processes that synthesize polymers traditionallyconsidered hydrolytically stable and non-biodegradable.

The monomers of the present invention may be polymerized to formabsorbable polymers that display excellent physical, chemical, andbiological properties, which make them useful in medical applications.In addition to being non-toxic in polymer form, the polymers of thepresent invention are expected to form non-toxic degradation products byhydrolytic chain cleavage under physiological conditions. The novelpolymers of the present invention are expected to have increased rate ofdegradation and bioresorption as well as controllable degradationprofile in comparison to the currently available polymers.

For example, a non-phenol containing amino acid, such as L-lysine, canbe functionalized to form a reactive compound, which can be polymerizedto form an absorbable polymer with a specific absorption profile.Similarly, each non-phenol containing amino acid described above can befunctionalized to form reactive monomers. The polymers derived fromthese monomers will have unique physical and biological properties withabsorption profiles that are controllable.

The absorbable polymers (e.g., polyesters, polyamides, polyester amides,polyurethanes, and polyanhydrides) of the present invention shoulddegrade faster and bioresorb faster than prior art polycarbonates andpolyarylates polymerized from desaminotyrosyltyrosine alkyl esters (seeU.S. Pat. Nos. 5,099,060, and 5,658,995). The polymers of the presentinvention are therefore expected to be useful as biomaterials in thosesituations that require a faster degradation and resorption rate thanthe previously achieved by known polymers of amino acids. Specificexamples of applications for which the polymers of the present inventionshould be particularly useful include scaffolds for tissue engineeringon which isolated cell populations may be transplanted in order toengineer new tissues and implantable drug delivery devices where apharmaceutically active moiety is admixed or in some way located withinthe polymeric matrix for slow release.

The present invention encompasses a variety of different polymers, someof which are copolymers. The polymers of the present invention include(a) polymers formed from one functionalized amino acid; (b) copolymersformed from more than one (e.g., 2, 3, or 4) type of functionalizedamino acid (e.g., a blend of functionalized amino acids that ispolymerized); (c) copolymers formed from at least one type offunctionalized amino acid having at least two active sites (e.g, 2 or 3)and a difunctional molecule (e.g., dicarboxylic acids, dialcohols,diisocyanates, amino-alcohols, hydroxy-carboxylic acids, and diamines);and (d) copolymers formed from at least one of the polymers of (a)-(c)and at least one lactone monomer (e.g., glycolide, lactide,ε-caprolactone, trimethylene carbonate, and p-dioxanone). The absorptionprofile of the polymers of the present invention will depend upon anumber of factors, including the functionalization species used and thenumber of functionalization species present on the functionalized aminoacid (e.g., 1-6). Glycolic acid based polymers should hydrolyze fasterthan dioxanone based, where as lactic acid and caprolactone basedpolymers should take much longer to hydrolyze than glycolic acid anddioxanone based polymers. The desired time range may be obtained byaltering the number and type of functionalization species as well as thenumber of different functionalized amino acids (e.g., a blend of two ormore functionalized amino acids). The desired time range will also beimpacted by moieties used for co-polymerization (e.g., difunctionalcompounds or lactone monomers).

As noted above, the functionalized amino acids of the present inventioncan be polymerized to form absorbable functionalized amino acid polymersof the present invention. If a linear polymer is desired, then only oneactive site is preferably present on the functionalized amino acid.Thus, if a linear polymer is desired from a functionalized amino acidwherein (X)_(a)—R′═H (i.e., a=0 and R′═H) and (Y)_(b)—R′ is H (i.e., b=0and R′═H), then it is advantageous to amidate either or both of theunmodified COOH and NH₂ groups. For example, O—(X)_(a)—R′ can beconverted to NR′R′ and/or (Y)_(b)—R′ can be converted to C(O)R′(provided that when (Y)_(b) is C(O), then R′ is other than H).

The functionalized amino acid polymers can be used in various medicalapplications described herein or can be further polymerized with lactonemonomers, such as glycolide, lactide, ε-caprolactone, trimethylenecarbonate, and p-dioxanone, and the resulting absorbable functionalizedamino acid/lactone copolymers can be used in the various medicalapplications described herein.

As noted above, more than one of the functionalized amino acids of thepresent invention can be blended and polymerized to form afunctionalized amino acid copolymer. The functionalized amino acidcopolymers can be used in various medical applications described hereinor can be further polymerized with lactone monomers, such as glycolide,lactide, ε-caprolactone, trimethylene carbonate, and p-dioxanone, andthe resulting absorbable polymers can also have the medical applicationsdescribed herein.

As noted above, the functionalized amino acids of the present inventionwith at least two reactive sites can be polymerized with difunctionalmolecules (e.g., dicarboxylic acids, dialcohols, diisocyanates,amino-alcohols, hydroxy-carboxylic acids, and diamines) to formabsorbable polymers, including but not limited to polyesters, polyesteramides, polyurethanes, polyamides, and polyanhydrides by simplepolycondensation reactions. The functionalized amino acid/difunctionalmolecule polymers can be used in various medical applications or can befurther polymerized with lactone monomers, such as glycolide, lactide,ε-caprolactone, trimethylene carbonate, and p-dioxanone, and theresulting absorbable polymers potential have the medical applicationsdescribed above.

In another example of the present invention, functionalized dihydroxyamino acids of the present invention can be used in the preparation ofpolyesters by reacting with dicarboxylic acid compounds. Dicarboxylicacids useful in the present invention have the following structure:

HOOC—R—COOH

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms

In another example of the present invention, functionalized dicarboxylicacid amino acids of the present invention can be used in the preparationof polyesters by reacting with the dialcohol (i.e., diol) compounds.Dialcohols useful in the present invention have the following structure:

HO—R—OH

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms.Alternatively, polyalkylene oxides have weight average molecular weightsfrom about 500-5,000 can be used as a diol (i.e., a polydiol). Suitablediols or polydiols for use in the present invention are diol or diolrepeating units with up to 8 carbon atoms. Examples of suitable diolsinclude 1,2-ethanediol (ethylene glycol); 1,2-propanediol (propyleneglycol); 1,3-propanediol; 1,4-butanediol; 1,5-pentanediol;1,3-cyclopentanediol; 1,6-hexanediol; 1,4-cyclohexanediol;1,8-octanediol; and, combinations thereof. Examples of polydiols includepolyethylene glycol and polypropylene glycol with weight averagemolecular weights of 500-5000.

In another example of the present invention, functionalized dihydroxyamino acids of the present invention can be used in the preparation ofpolyurethanes by reacting with diisocyante compounds. Examples ofdiisocyanates include hexamethylene diisocyante, lysine diisocyanate,methylene diphenyl diisocyanate (e.g., MDI), hydrogenated MDI (e.g.,methylene dicyclohexyl diisocyanate), and isophorone diisocyanate.

In another example of the present invention, functionalizedhydroxy-amino amino acids of the present invention can be used in thepreparation of polyesteramides by reacting with dicarboxylic acidcompounds described above.

In another example of the present invention, functionalized dicarboxylicacid amino acids of the present invention can be used in the preparationof polyesteramides by reacting with the amino-alcohol compounds.Amino-alcohols useful in the present invention have the followingstructure:

HO—R—NH₂

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms.

In another example of the present invention, functionalizedhydroxy-carboxylic acid amino acids of the present invention can be usedin the preparation of polyesters by reacting with hydroxycarboxylic acidcompounds. Hydroxycarboxylic acids useful in the present invention havethe following structure:

HO—R—COOH

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms,

In another example of the present invention, functionalizedamino-carboxylic acid amino acids of the present invention can be usedin the preparation of polyesteramides by reacting with thehydroxycarboxylic acid compounds described above.

In another example of the present invention, functionalized dicarboxylicacid amino acids of the present invention can be used in the preparationof polyamides by reacting with the diamine compounds. Diamines useful inthe present invention have the following structure:

H₂N—R—NH₂

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms.Alternatively, polyalkylene oxides that are diamines with weight averagemolecular weights from about 500-5,000 can be used.

In another example of the present invention, functionalized dicarboxylicacid amino acids of the present invention can be used in the preparationof polyanhydrides by reacting with the dicarboxylic acid compoundsdescribed above.

The functionalized amino acids of the present invention having more thantwo reactive groups (e.g., 3) are expected to be useful in thepreparation of cross linked hydrogels and are prepared

Examples of polymers of the present invention have weight-averagemolecular weights above about 20,000 daltons or above about 100,000daltons, calculated from gel permeation chromatography (GPC) relative topolystyrene standards in tetrahydrofuran (THF) without furthercorrection.

The polymers of the present invention should be able to be processed byknown methods commonly employed in the field of synthetic polymers toprovide a variety of useful articles with valuable physical and chemicalproperties. The useful articles can be shaped by conventionalpolymer-forming techniques such as extrusion, compression molding,injection molding, solvent casting, and wet spinning. Shaped articlesprepared from the polymers are expected to be useful as degradabledevices for medical implant applications.

The present invention also relates to a composition, comprising: two ormore functional amino acids of the present invention.

The present invention also relates to a composition, comprising: atleast one functionalized amino acid, wherein the composition is suitablefor use as at least one of the following: (a) a solvent for drugs; (b) anutritional compound; (c) a cosmetic: and, (d) a pharmaceutical. Each ofthe compositions may further comprise an additional component suitablefor such composition. For example, when the composition is suitable foruse as a cosmetic it may further comprise: one or more cosmeticingredients. Also, when the composition is suitable for use as apharmaceutical it may further comprise: one or more pharmaceuticallyacceptable excipients.

The implantable medical devices of the present invention, comprise: atleast one absorbable polymer of the present invention. For example, apolymer of the present invention can be combined with a quantity of abiologically or pharmaceutically active compound sufficient to betherapeutically effective as a site-specific or systemic drug deliverysystem (see Gutowska et al., J. Biomater. Res., 29, 811-21 (1995) andHoffman, J. Controlled Release, 6, 297-305 (1987)). Another example ofthe present invention is a method for site-specific or systemic drugdelivery by implanting in the body of a patient in need thereof animplantable drug delivery device comprising a therapeutically effectiveamount of a biologically or a physiologically active compound incombination with at least one absorbable polymer of the presentinvention.

In another example, at least one polymer of the present invention isformed into a porous device (see Mikos et al., Biomaterials, 14, 323-329(1993) or Schugens et al., J. Biomed. Mater. Res., 30, 449-462 (1996))to allow for the attachment and growth of cells (see Bulletin of theMaterial Research Society, Special Issue on Tissue Engineering (GuestEditor: Joachim Kohn), 21(11), 22-26 (1996)). Thus, the presentinvention provides a tissue scaffold comprising a porous structure forthe attachment and proliferation of cells either in vitro or in vivoformed from at least one absorbable polymer of the present invention

The present invention also relates to an article (e.g., an implantablemedical device), comprising: a metal or polymeric substrate havingthereon a coating, wherein the coating, comprises: at least one polymerof the present invention.

The present invention also relates to a molded article prepared from atleast one polymer of the present invention.

The present invention also relates to a controlled drug delivery system,comprising: at least one polymer of the present invention physicallyadmixed with a biologically or pharmacologically active agent. Forexample, the controlled drug delivery system can comprise: abiologically or pharmacologically active agent coated with at least onepolymer of the present invention.

The present invention also relates to a controlled drug delivery system,comprising: a biologically or pharmacologically active agent physicallyembedded or dispersed into a polymeric matrix formed from at least onepolymer of the present invention.

The present invention also relates to a tissue scaffold having a porousstructure for the attachment and proliferation of cells, either in vitroor in vivo, formed from one least one polymer of the present invention.

The present invention also relates to a composition, comprising: atleast one polymer of the present invention, which has been furtherpolymerized with at least one lactone monomer selected from: glycolide,lactide, p-dioxanone, trimethylene carbonate, and caprolactone.

The present invention also relates to an implantable biomedical device,comprising: at least one polymer that has been further polymerized withat least one lactone monomer.

The present invention also relates to a biodegradable chewing gumcomposition, comprising: an effective amount of at least one polymerthat has been further polymerized with at least on lactone monomer.

The present invention also relates to an article (e.g., an implantablemedical device), comprising: a metal or polymeric substrate and havingthereon a coating, wherein said coating comprises at least one polymerthat has been further polymerized with at least one lactone monomer.

The present invention also relates to a molded article prepared from atleast one polymer that has been further polymerized with at least onelactone monomer.

The present invention also relates to a monofilament or multifilamentprepared from at least one polymer that has been further polymerizedwith at least one lactone monomer.

The present invention also relates to a controlled drug delivery system,comprising: at least one polymer that has been further polymerized withat least one lactone monomer, which has been physically admixed with abiologically or pharmacologically active agent.

The present invention also relates to a controlled drug delivery system,comprising: a biologically or pharmacologically active agent physicallyembedded or dispersed into a polymeric matrix formed from at least onepolymer that has been further polymerized with at least one lactonemonomer.

The present invention also relates to a tissue scaffold having a porousstructure for the attachment and proliferation of cells, either in vitroor in vivo, formed from at least one polymer that has been furtherpolymerized with at least one lactone monomer.

The present invention also relates to low molecular weight polymers oroligomers of the functionalized amino acids of the present inventionthat are further reacted to form reactive end groups (e.g., isocyanates,expoxides, and acrylates). Low-molecular weight polymers or oligomers asused herein means a polymer having a number average molecular weight ofabout 500-20,000 or 500-10,000. For example, some of the functionalizednon-phenolic amino acids behave chemically like diols. They can bereacted with dicarboxylic acids to form polyesters, which are usuallyhydroxyterminated. These hydroxyterminated oligomers can be furtherreacted to form isocyanates, epoxides and acrylates. Similarly thefunctionalized non-phenolic amino acids can be reacted with isocyanatesto make urethanes. Thus, the present invention also includes acomposition, comprising: at least one polymer of the present invention,which has been further reacted to form reactive end groups.

The present invention also relates to polymers made from functionalizedamino acids that have been sterilized by cobalt-60 radiation, electronbeam radiation, and/or ethylene oxide.

“Bioabsorbable” or “absorbable” as used herein means that the materialreadily reacts or enzymatically degrades upon exposure to bodily tissuefor a relatively short period of time, thereby experiencing asignificant weight loss in that short period of time. Completebioabsorption/absorption should take place within twelve months,although it may be complete within nine months or within six months. Inthis manner, the polymers of the present invention can be fabricatedinto medical and surgical devices, which are useful for a vast array ofapplications requiring complete absorption within a relatively shorttime period.

The biological properties of the bioabsorbable polymers of the presentinvention used to form a device or part thereof, as measured by itsabsorption rate and its breaking strength retention in vivo (BSR), canbe varied to suit the needs of the particular application for which thefabricated medical device or component is intended. This can beconveniently accomplished by varying the ratio of components of thepolymer chosen.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to treat the desired indication.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.

Polymers of the present invention may be made in the form of randomcopolymers or block copolymers. A coupling agent may also be added tothe polymers of the present invention. A coupling agent is a reagentthat has a least two functional groups that are capable of covalentlybonding to two different monomers. Examples of coupling agents includetrifunctional or tetrafunctional polyols, oxycarboxylic acids, andpolybasic carboxylic acids (or acid anhydrides thereof). Other couplingagents include the difunctional groups (e.g., diols, diacids, diamines,and hydroxy-acids) previously discussed. The addition of the couplingagents causes the branching of long chains, which can impart desirableproperties in the molten state to the pre-polymer. Examples ofpolyfunctional coupling agents include trimethylol propane, glycerin,pentaerythritol, malic acid, citric acid, tartaric acid, trimesic acid,propane tricarboxylic acid, cyclopentane tetracarboxylic anhydride, andcombinations thereof.

A “pre-polymer” is a low-molecular weight polymer, as previouslydefined, that have reactive endgroups (e.g., hydroxy groups) that can befurther reactive with, for example, the lactone monomers.

The amount of coupling agent to be added before gelation occurs is afunction of the type of coupling agent used and the polymerizationconditions of the polymer or molecular weight of the pre-polymer towhich it is added. Generally in the range of from about 0.1 to about 10mole percent of a trifunctional or a tetrafunctional coupling agent maybe added based on the moles of polymers present or anticipated from thesynthesis.

The polymerization of a polyester of the present invention can beperformed under melt polycondensation conditions in the presence of anorganometallic catalyst at elevated temperatures. The organometalliccatalyst can be a tin-based catalyst (e.g., stannous octoate or dibutyltin oxide). The catalyst can be present in the mixture at a mole ratioof diol, dicarboxylic acid, and optionally lactone monomer to catalystwill be in the range of from about 15,000/1 to 80,000/1. The reactioncan be performed at a temperature not less than about 120° C. underreduced pressure. Higher polymerization temperatures may lead to furtherincreases in the molecular weight of the copolymer, which may bedesirable for numerous applications. The exact reaction conditionschosen will depend on numerous factors, including the properties of thepolymer desired, the viscosity of the reaction mixture, and the glasstransition temperature and softening temperature of the polymer. Desiredreaction conditions of temperature, time and pressure can be readilydetermined by assessing these and other factors. Generally, the reactionmixture will be maintained at about 220° C. The polymerization reactioncan be allowed to proceed at this temperature until the desiredmolecular weight and percent conversion is achieved for the copolymer,which will typically take about 15 minutes to 24 hours. Increasing thereaction temperature generally decreases the reaction time needed toachieve a particular molecular weight.

Polymerization conditions for the preparation of other types of polymersof the present invention (e.g., polyamides and polyurethanes) aredescribed in the literature. Those skilled in the art will recognizethat the polymers described herein can be made from known procedures.

Copolymers of the absorbable polymers of the present invention can beprepared by preparing a pre-polymer under melt polycondensationconditions, then adding at least one lactone monomer or lactonepre-polymer. The mixture could then be subjected to the desiredconditions of temperature and time to copolymerize the pre-polymer withthe lactone monomers.

A lactone pre-polymer is a pre-polymer formed by ring openingpolymerization with a known initiator (e.g., ethylene glycol, diethyleneglycol, glycerol, or other diols or triols).

The molecular weight of the pre-polymer as well as its composition canbe varied depending on the desired characteristic, which the pre-polymeris to impart to the copolymer. For example, the pre-polymers of thepresent invention, from which the copolymer is prepared, generally havea molecular weight that provides an inherent viscosity between about 0.2to about 2.0 deciliters per gram (dl/g) as measured in a 0.1 g/dlsolution of hexafluoroisopropanol at 25° C. Those skilled in the artwill recognize that the pre-polymers described herein can also be madefrom mixtures of more than one diol or dicarboxylic acid.

One of the beneficial properties of the polyesters of the presentinvention is that the ester linkages are hydrolytically unstable, andtherefore the polymer is bioabsorbable because it readily breaks downinto small segments when exposed to moist bodily tissue. In this regard,while it is envisioned that co-reactants could be incorporated into thereaction mixture of the dicarboxylic acid and the diol for the formationof the polyester pre-polymer, it is preferable that the reaction mixturedoes not contain a concentration of any co-reactant which would renderthe subsequently prepared polymer nonabsorbable. The reaction mixturecan be substantially free of any such co-reactants if the presencethereof results in a nonabsorbable polymer.

The polymers of the present invention can be melt processed by numerousmethods to prepare a vast array of useful devices. These polymers can beinjection or compression molded to make implantable medical and surgicaldevices, especially wound closure devices.

Alternatively, the polymers can be extruded to prepare fibers. Thefilaments thus produced may be fabricated into sutures or ligatures,attached to surgical needles, packaged, and sterilized by knowntechniques. The polymers of the present invention may be spun asmultifilament yarn and woven or knitted to form sponges or gauze, (ornon-woven sheets may be prepared) or used in conjunction with othermolded compressive structures as prosthetic devices within the body of ahuman or animal where it is desirable that the structure have hightensile strength and desirable levels of compliance and/or ductility.Examples include tubes, including branched tubes, for artery, vein, orintestinal repair, nerve splicing, tendon splicing, sheets for typing upand supporting damaged surface abrasions, particularly major abrasions,or areas where the skin and underlying tissues are damaged or surgicallyremoved.

Additionally, the polymers can be molded to form films which, whensterilized, are useful as adhesion prevention barriers. Anotheralternative processing technique for the polymers of the presentinvention includes solvent casting, particularly for those applicationswhere a drug delivery matrix is desired.

The polymers of the present invention can be used to coat a surface of asurgical article to enhance the lubricity of the coated surface. Thepolymer may be applied as a coating using conventional techniques. Forexample, the polymer may be solubilized in a dilute solution of avolatile organic solvent (e.g. acetone, methanol, ethyl acetate, ortoluene), and then the article can be immersed in the solution to coatits surface. Once the surface is coated, the surgical article can beremoved from the solution where it can be dried at an elevatedtemperature until the solvent and any residual reactants are removed.

For coating applications, the polymer should exhibit an inherentviscosity, as measured in a 0.1 gram per deciliter (g/dl) ofhexafluoroisopropanol (HFIP), between about 0.05-2.0 dl/g or about0.10-0.80 dl/g. If the inherent viscosity were less than about 0.05dl/g, then the polymer may not have the integrity necessary for thepreparation of films or coatings for the surfaces of various surgicaland medical articles. On the other hand, it is possible to use polymerswith an inherent viscosity greater than about 2.0 dl/g, though it may bedifficult to do so.

Although numerous surgical articles (including but not limited toendoscopic instruments) can be coated with the polymer of the presentinvention to improve the surface properties of the article, specificsurgical articles include surgical sutures, stents, and needles. Forexample the surgical article can be a suture, which can be attached to aneedle. The suture can be a synthetic absorbable suture. These suturesare derived, for example, from homopolymers and copolymers of lactonemonomers such as glycolide, lactide, ε-caprolactone, 1,4-dioxanone, andtrimethylene carbonate. The suture can be a braided multifilament suturecomposed of polyglycolide or poly(glycolide-co-lactide).

The amount of coating polymer to be applied on the surface of a braidedsuture can be readily determined empirically, and will depend on theparticular copolymer and suture chosen. Ideally, the amount of coatingcopolymer applied to the surface of the suture may range from about0.5-30 percent of the weight of the coated suture or from about 1.0-20weight percent, or from 1-5 percent by weight. If the amount of coatingon the suture were greater than about 30 weight percent, then it mayincrease the risk that the coating may flake off when the suture ispassed through tissue

Sutures coated with the polymers of the present invention are desirablebecause they have a more slippery feel, thus making it easier for thesurgeon to slide a knot down the suture to the site of surgical trauma.In addition, the suture is more pliable, and therefore is easier for thesurgeon to manipulate during use. These advantages are exhibited incomparison to sutures which do not have their surfaces coated with thepolymer of the present invention.

When the article of the present invention is a metal stent, the amountof coating applied to the surface of the article is an amount whichcreates a layer with a thickness ranging, for example, between about 2-20 microns on the stent or about 4-8 microns. If the amount of coatingon the stent were such that the thickness of the coating layer wasgreater than about 20 microns, or if the thickness was less than about 2microns, then the desired performance of the stent as it is passedthrough tissue may not be achieved.

When the article of the present invention is a surgical needle, theamount of coating applied to the surface of the article is an amountwhich creates a layer with a thickness ranging, for example, betweenabout 2-20 microns on the needle or about 4-8 microns. If the amount ofcoating on the needle were such that the thickness of the coating layerwas greater than about 20 microns, or if the thickness was less thanabout 2 microns, then the desired performance of the needle as it ispassed through tissue may not be achieved.

The polymers of the present invention can also be used as apharmaceutical carrier in a drug delivery matrix. To form this matrixthe polymer can be mixed with a therapeutic agent to form the matrix.There are a variety of different therapeutic agents, which can be usedin conjunction with the polymers of the invention. In general,therapeutic agents which may be administered via the pharmaceuticalcompositions of the invention include, antiinfectives such asantibiotics and antiviral agents; analgesics and analgesic combinations;anorexics; antihelmintics; antiarthritics; antiasthmatic agents;anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals;antihistamines; antiinflammatory agents; antimigraine preparations;antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; diuretics; vasodilatorsincluding general coronary, peripheral and cerebral; central nervoussystem stimulants; cough and cold preparations, including decongestants;hormones such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives; muscle relaxants;parasympatholytics; psychostimulants; sedatives; and tranquilizers; andnaturally derived or genetically engineered proteins, polysaccharides,glycoproteins, or lipoproteins.

The drug delivery matrix may be administered in any suitable dosage formincluding orally, parenterally, subcutaneously as an implant, vaginally,or as a suppository. Matrix formulations containing the polymers of thepresent invention may be formulated by mixing one or more therapeuticagents with the polymer. The therapeutic agent, may be present as aliquid, a finely divided solid, or any other appropriate physical form.Typically, but optionally, the matrix will include one or moreadditives, e.g., nontoxic auxiliary substances such as diluents,carriers, excipients, or stabilizers. Other suitable additives may beformulated with the polymers of the present invention andpharmaceutically active agent. If water is to be used, then it can beuseful to add it just before administration.

The amount of therapeutic agent will be dependent upon the particulardrug employed and medical condition being treated. Typically, the amountof drug represents about 0.001%-70%, 0.001%-50%, or 0.001%-20% by weightof the matrix.

The quantity and type of polymer incorporated into a composition (e.g.,parenterally delivered composition) will vary depending on the releaseprofile desired and the amount of drug employed. The product may containblends of polymers of the present invention to provide the desiredrelease profile or consistency to a given formulation.

The polymers of the present invention, upon contact with body fluidsincluding blood or the like, undergoes gradual degradation (mainlythrough hydrolysis) with concomitant release of the dispersed drug for asustained or extended period (as compared to the release from anisotonic saline solution). This can result in prolonged delivery (e.g.,over 1-2,000 hours or 2-800 hours) of effective amounts (e.g., 0.0001mg/kg/hour to 10 mg/kg/hour) of the drug. This dosage form can beadministered as is necessary depending on the subject being treated, theseverity of the affliction, and the judgment of the prescribingphysician.

Individual formulations of drugs and polymers of the present inventionmay be tested in appropriate in vitro and in vivo models to achieve thedesired drug release profiles. For example, a drug could be formulatedwith a polymer of the present invention and orally administered to ananimal. The drug release profile could then be monitored by appropriatemeans such as, by taking blood samples at specific times and assayingthe samples for drug concentration. Following this or similarprocedures, those skilled in the art will be able to formulate a varietyof formulations.

Functionalization

The functionalized amino acids of the present invention are typicallyprepared from a starting non-phenolic amino acid as shown below (whereinthe OH and funcationalized OH groups are optionally present).

The desired X and Y groups can be added using methods known to those ofskill in the art, some of which are described below.

It is well known how to functionalize an amino, acid, or hydroxyl groupof an amino acid. Thus, the functionalized amino acids of the presentinvention can be prepared according to any recognized method.

Biodegradable Chewing Gums

After conventional chewing gum is chewed, the gum cud that remains thatmust be discarded. Unfortunately, conventional gum cuds can easilyadhere to any dry surface, such as wood, concrete, paper and cloth. Whengum cuds are improperly discarded, they can be difficult to remove fromsuch surfaces, causing some environmental concerns. Recently, there hasbeen a move to develop a chewing gum which is either ingestible or thatcreates a gum cud that is easily removable and degradable. Therefore,one of the objects of the present invention is to develop hydrolyzableand flexible elastomers that can be used in conventional and specializedbiomedical chewing gum. Some of the compositions of the presentinvention can provide improved chewing gum and gum bases. The improvedchewing gum and gum bases are biodegradable and do not causeenvironmental concerns if improperly discarded.

Bioactive Formulations

In other aspects of the present invention some functionalizednon-phenolic amino acids of the present invention are furthermanufactured into formulations suitable for oral, rectal, parenteral(for example, subcutaneous, intramuscular, intradermal, or intravenous),transdermal, vitreal or topical administration. The most suitable routein any given case will depend on the nature and severity of thecondition being treated and on the nature of the particular activecompound that is being used. The formulations of a pharmaceuticalcomposition are typically admixed with one or more pharmaceutically orveterinarially acceptable carriers and/or excipients as are well knownin the art.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or a suspension in an aqueous or non-aqueousliquid; or as an oil-in-water or water-in-oil emulsion.

Compositions of the present invention suitable for parenteraladministration conveniently comprise sterile aqueous preparations of theactive compounds, which preparations are preferably isotonic with theblood of the intended recipient.

Formulations suitable for rectal administration are preferably presentedas unit dose suppositories.

Formulations suitable for ocular or vitreal administration may bepresented as bioabsorbable coatings for implantable medical devices,injectables, liquids, gels or suspensions.

Formulations or compositions suitable for topical administration to theskin preferably take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Examples of carriers that conventionally usedinclude Vaseline, lanoline, polyethylene glycols, alcohols, andcombination of two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time.

The active compounds may be provided in the form of foodstuffs ornutrition supplements, such as being added to, admixed into, coated,combined or otherwise added to a foodstuff. The term foodstuff is usedin its widest possible sense and includes liquid formulations such asdrinks including dairy products, biodegradable chewing gums, and otherfoods, such as health bars, desserts, etc. Food formulations containingcompounds of the invention can be readily prepared according to standardpractices.

Compounds of the formula used as medicaments or pharmaceuticals aretypically administered in a manner and amount as is conventionallypracticed. See, for example, Goodman and Gilman, The PharmaceuticalBasis of Therapeutics, current edition.

Compounds of the present invention have potent antioxidant activity andincreased acidity of their non-phenolic component, as well as theimproved biodegradation provided by the functionalization, and thus findwide application in pharmaceutical and veterinary uses, in cosmeticssuch as more effective skin creams to prevent skin ageing, in sunscreens, in foods, health drinks, nutritional supplements, shampoos, andthe like.

Examples of preparing the functionalized amino acids of the presentinventionare provided for some embodiments of the current invention. Itcan be extended to many other species. This selection is not meant tolimit the scope of the invention in any way. Other variations in theprocedure may be readily apparent to those skilled in the art.

EXAMPLES

The melting point was measured for all the products by using Polmon (MP96) melting point apparatus, and the melting point was found to be134.5-135.5° C. (lit 135-139° C.). For all the products, NMR was runusing Varian 200 MHz and tetramethylsilane as an internal standard.

Example-1 L-Lysine methyl ester dihydrochloride

To a mixture of L-lysine HCl (100 grams, 547.49 mmol) in methanol (1.75lit) at 0° C. was bubbled dry HCl for 7 hours. The crude solid productwas filtered, dried to get pure 1 (117 grams, 91.6%) as a white powder.

M.p: 204.5-206° C. (lit 213-215° C.). ¹H NMR (DMSO-d₆) δ 1.48(m,2H,CH₂), 1.68 (m,2H,CH₂), 1.90 (m,2H,CH₂), 2.80 (m,2H,CH₂), 3.78(s,3H, Ester), 4.00 (t,1H,CH), 8.20 (Bs, 2H,NH₂), 8.70 (Bs,2H,NH₂).

Example-2 2,6-Bis-(2-benzyloxy-acetylamino)-hexanoic acid methyl ester

To a mixture of L-lysine methyl ester dihydrochloride (50 grams, 214.4mmol), triethylamine (131 grams, 1.294 moles) in ethyl acetate (750 mL)at room temperature was added benzyloxy acetyl chloride (120 grams,650.4 mmol) drop wise. The mixture was further stirred at roomtemperature for 2 hours. The solids were filtered off. The organic phasewas washed with 5% sodium bicarbonate (2×100 mL), water (2×100 mL),dried over sodium sulphate and distilled. The crude 2 was purified bycolumn chromatography on silica gel using Benzene: Ethyl acetate (9:1)to get pure 2 (30 grams, 31.8%) as a white powder.

M.p: 62-65° C. ¹H NMR (CDCl₃) δ 1.36 (m,2H,CH₂), 1.56 (m,2H,CH₂), 1.76(m,2H,CH₂), 3.28 (m,2H,CH₂) 3.78 (s,3H,Ester), 3.96 (m,3H,CH₂ & CH),4.60 (m,6H,CH₂×3), 6.60 (bt,1H,NH), 7.06 (bd,1H,NH), 7.34 (m,10H,Ar).

Example-3 2,6-Bis-(2-hydroxy-acetylamino)-hexanoic acid methyl ester

2,6-Bis-(2-benzyloxy-acetylamino)-hexanoic acid methyl ester (38 grams,86.36 mmol) was dissolved in methanol (250 mL) in a pressure vessel,palladium on carbon (10%, 50% wet, 20 grams) added and the mixturestirred under an atmosphere of Hydrogen (4 kg) for 16 hours. Thecatalyst was removed by filtration and distilled off methanol. The crude3 was purified by column chromatography on silica gel using chloroform:methanol (9:1) to get pure 3 (17 grams, 71.4%) as a light yellow syrup.

¹H NMR (DMSO-d₆) δ 1.25 (m,2h,CH₂), 1.40 (m,2H,CH₂), 1.70 (m,2h,CH₂),3.60 (m,2h,CH₂), 3.61 (s,3h,Ester), 3.75 (s,2H,CH₂), 3.83 (s,2H,CH₂),4.28 (q,lh,CH), 5.50 (bs,2H₂OH), 7.70 (t,1H,NH), 7.90 (d,1H,NH).

Example-4 Lysine Amide diol Polymer

To a solution of Lysine diisocyanate (3.84 grams, 18.11 mmol) in drydimethyl formamide (5 mL) under N₂ atmosphere was added a solution2,6-Bis-(2-hydroxy-acetylamino)-hexanoic acid methyl ester (5 grams,18.11 mmol) in dry dimethyl formamide (15 mL) followed by dibutyl tindilaurate (0.1 grams, 0.158 mmol) and the whole heated to 85-90° C. for24 hours. The reaction mass was cooled to room temperature and slowlypoured on to Ice water (50 mL). The polymer was extracted in to ethylacetate (2×50 mL), dried over sodium sulphate and distilled.

IR: 1718 cm⁻¹; 1660 cm⁻¹.

Example-5 2,6-Bis-[2-(2-benzyloxy-acetoxy)-acetylamino]-hexanoic acidmethyl ester

To a mixture of 2,6-Bis-(2-hydroxy-acetylamino)-hexanoic acid methylester (2 grams, 7.24 mmol), triethylamine (3.92 grams, 38.73 mmoles) inethyl acetate (10 mL) at room temperature was added benzyloxy acetylchloride (4.7 grams, 25.47 mmol) drop wise. The mixture was furtherstirred at room temperature for 10 hours. The solids were filtered off.The organic phase was washed with 5% sodium bicarbonate (2×20 mL), water(2×20 mL), dried over sodium sulphate, and distilled. The crude 5 waspurified by column chromatography on silica gel using chloroform:ethylacetate (9:1) to get pure 5 (2.1 grams, 52.8%) as a Light yellow syrup.

Example-66-[2-(2-Hydroxy-acetoxy)-acetylamino]-2-[2-(3-hydroxy-propionyloxy)-acetylamino]-hexanoicacid methyl ester

This can be prepared by debenzylation of2,6-Bis[2-(2-benzyloxy-acetoxy)-acetylamino]-hexanoic acid methyl ester(Example 5).

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

1. A functionalized amino acid compound selected from:

wherein: X is selected from: —CH₂COO—; —CH(CH₃)COO—; —CH₂CH₂OCH₂COO—; CH₂CH₂CH₂CH₂CH₂COO—; —(CH₂)_(y)COO—; and, —(CH₂CH₂O)_(z)CH₂COO—, where y is selected from 2, 3, 4, and 6-24 and z is selected from 2-24; Y is selected from: —COCH₂O—; —COCH(CH₃)O—; —COCH₂OCH₂CH₂O—; —COCH₂CH₂CH₂CH₂CH₂O—; —CO(CH₂)_(m)O—; and, —COCH₂O(CH₂CH₂O)_(n)—, where m is selected from 2-4 and 6-24 and n is selected from 2-24; R′ is selected from hydrogen, benzyl, and a straight-chained C₁₋₆ alkyl; a and b are independently selected from 1-4, provided that a+b total from 2-6; provided that: (a) when the remaining portion of the amino acid is CH₂ and (X)_(a)—R′ is CH₂CO₂H, then (Y)_(b)—R′ is other than C(O)CH₂OH; or, (b) when the remaining portion of the amino acid is CH₂ and (Y)_(b)—R′ is C(O)CH₂OH, then (X)_(a)—R′ is other than CH₂CO₂H.
 2. (canceled)
 3. (canceled)
 4. A compound according to claim 3, wherein: y is selected from 2, 3, and 4; z is selected from 2, 3, and 4; m is selected from 2, 3, and 4; and n is selected from 2, 3, and
 4. 5. A compound according to claim 1, wherein: X is selected from: —CH₂COO—; —CH(CH₃)COO—; —CH₂CH₂OCH₂COO—; and, —CH₂CH₂CH₂CH₂CH₂COO—; Y is selected from: —COCH₂O—; —COCH(CH₃)O—; —COCH₂OCH₂ CH₂O—; —COCH₂CH₂CH₂CH₂CH₂O—; and, a and b are independently selected from 1-2.
 6. A compound according to claim 5, wherein: R′ is selected from hydrogen, benzyl, and a straight-chained or branched C₁₋₄ alkyl; and, a and b are independently selected from 1-2, provided that a+b total from 2-3.
 7. A compound according to claim 6, wherein: R′ is selected from hydrogen, benzyl, and CH₃.
 8. A compound according to claim 1, wherein: X is —CH₂COO—; Y is —COCH₂O—; R′ is selected from hydrogen, benzyl, and a straight-chained or branched C₁₋₄ alkyl; and, a and b are independently selected from 1-2.
 9. A compound according to claim 8, wherein: R′ is selected from hydrogen, benzyl, and CH₃; and, a and b are
 1. 10-25. (canceled)
 26. A functionalized amino acid compound of claim 1, wherein the compound is:


27. A functionalized amino acid compound of claim 1, wherein the compound is:


28. A functionalized amino acid compound of claim 1, wherein the compound is:


29. A functionalized amino acid compound of claim 1, wherein the compound is:


30. A functionalized amino acid compound of claim 1, wherein the compound is:


31. A functionalized amino acid compound of claim 1, wherein the compound is:


32. A functionalized amino acid compound of claim 1, wherein the compound is:


33. A functionalized amino acid compound of claim 1, wherein the compound is:


34. A functionalized amino acid compound of claim 1, wherein the compound is:


35. A functionalized amino acid compound of claim 1, wherein the compound is:


36. A functionalized amino acid compound of claim 1, wherein the compound is:


37. A functionalized amino acid compound of claim 1, wherein the compound is:


38. A functionalized amino acid compound of claim 1, wherein the compound is:


39. A functionalized amino acid compound of claim 1, wherein the compound is:


40. A functionalized amino acid compound of claim 1, wherein the compound is:


41. A functionalized amino acid compound of claim 1, wherein the compound is:


42. A functionalized amino acid compound of claim 1, wherein the compound is:


43. A functionalized amino acid compound of claim 1, wherein the compound is:


44. A functionalized amino acid compound of claim 1, wherein the compound is: 